Core 4: Pharmacokinetic, Biodistribution, and Biocompatibility Core The Pharmacokinetic, Biodistribution and Biocompatibilty Core (PBBC) has three tasks. Our primary mission is to determine the pharmacokinetics, biodistribution and biocompatibility in rodents of nanocarriers prepared by Projects 1 and 4. We will confirm particle diameter, charge and endotoxin level in the formulation. We will examine the biodistribution after intravenous administration at the organ and cell level using radiolabels and fluorescent tracers. For selected formulations, we will also examine the biodistribution after intratracheal and intracerebral administration particularly those nanoparticles from Project 4. We will determine the biocompatibility of formulations that have promising pharmacokinetic or distribution characteristics, such as a blood elimination half-life greater than eight hours or unusual organ distributions, such as brain localization. For biocompatible formulations, we will determine their distribution properties in a solid tumor model in rodents. Our second task is to provide novel, low pH-sensitive diorthoester PEG conjugates to consortium membranes for incorporation into nanocarriers prepared in their groups. The PEG diorthoesters can be used as a bioreversible coating to improve the nanocarrier biocompatibility. The final task is to use a sequential assembly solution process to prepare multifunctional, targeted nanolipid particles (NLP). The Combinatorial Library Research Core will provide the targeting ligand. The NLP incorporate a therapeutic agent and an imaging agent for tracking NLP distribution in animals. Such particles will enable the estimation of the dose delivered to the target site in living animals. These NLP will be supplied to the Small Animal Imaging Core and to the Animal Model Core to determine NLP delivery potential in specific models. By accomplishing these tasks we will provide a detailed, unbiased, objective testing of leading nanoparticle candidates. This will ensure quick feedback to the consortium participants of potential problems and promising directions. Hence, nanocarriers with suitable biodistribution and biocompatibility profiles would be more rapidly identified for further study in large animals and humans.